In some human malignancies tumor progression has been associated with amplification or increased expression of either myc or ras oncogenes. We used an N-nitrosomethylurea (NMU)-induced rat mammary carcinoma model to study ras expression in primary vs. metastatic tumors. Evaluation of a primary tumor and ten lung metastases derived from this primary revealed the following findings. There was considerable variability in the ras-specific DNA levels among the individual metastases some were lower, while others were higher than the parent primary tumor. Similarly, the ras RNA levels were variable, with three of ten metastases showing barely detectable ras expression by slot blot analysis. There was no significant difference in the ras DNA levels between normal breast and the neoplastic tissues, either primary metastatic, nonmetastatic, or metastases. Furthermore, there was much less variability in the ras levels of the NMU-tumors after multiple passages in syngeneic rats than in autochthonous tumors. Ongoing studies on metalloproteinase expression by the NMU-tumors have revealed that type IV collagenolytic activity was higher in the tumors than in normal mammary glands. However, the collagenolytic activity in metastases did not differ from the primary tumor. To complete the project the metalloproteinases present in tumor lysates and expressed by cell lines derived from primary tumor and metastases will be studied by gelatin gel electrophoresis. Lastly, comparison of ras expression in different parts of primary tumors and metastases will be made by immunoperoxidase staining of the p21 ras product using antibody raised against the p21 protein.